Diet and Gastrointestinal Cancer Risk in African Americans and Rural Africans

非裔美国人和非洲农村人的饮食和胃肠癌风险

• 批准号: 8033159
• 负责人: Stephen J.D. O'Keefe
• 金额: $ 56.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-04 至 2013-01-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8033159
• 关键词: African; African American; American; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Archaea; Area; Bacteria; Biological Markers; Biological Preservation; Butyrates; Cancer Etiology; Carbohydrates; Carcinogens; Cells; Cessation of life; Cholesterol; Chronic; Colon Carcinoma; Communities; Complex; Consumption; DNA Damage; Death Rate; Development; Diagnosis; Diet; Diet Modification; Dietary Factors; Dietary Intervention; Dietary intake; Disease; Eating; Environment; Epithelial; Equilibrium; Excretory function; Exposure to; Fatty acid glycerol esters; Fiber; Folate; Gases; Gene Expression; Genes; Growth; Health; Health Care Costs; Hydrogen; Hydrogen Sulfide; Incidence; Infection; Inflammation; Inflammatory; Injury; Intake; Intervention Studies; Investigation; Knowledge; Lactobacillus; Lead; Link; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Measurement; Meat; Mediating; Metabolic; Metabolism; Metagenomics; Methane; Methanobacteria; Microarray Analysis; Mind; Morbidity - disease rate; Mucositis; Mucous Membrane; Natural Selections; Participant; Pathway interactions; Pharmaceutical Preparations; Population; Population Growth; Production; Property; Race; Reducing diet; Reporting; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Rural; Starch; Sulfur-Reducing Bacteria; Supervision; Techniques; Testing; Time; Variant; Volatile Fatty Acids; bile salts; cancer risk; caucasian American; comparative; cooking; cytotoxic; density; design; diet and cancer; follow-up; high risk; human subject; insight; microbiome; middle age; mortality; novel; population based; prevent; programs; red meat consumption; research study; statistics; sulfate reducing bacteria

DESCRIPTION (provided by applicant): Geographical variations in cancer incidence can be attributed to environmental causes in general, and to diet, in particular. We are concerned that the reason why African Americans (AAs) have the highest incidence (c1:70,000 of the population) and death rate from colon cancer in the USA is due to dietary factors as native Africans, who consume a very different diet, hardly ever get the disease (<1: 100,000). Studies of ours in the 2 communities, supported by a wealth of experimental evidence, have suggested that the explanation may lie in the high dietary intake of red meat by AAs which increases microbiota populations of sulfur-reducing bacteria (SRBs), which produce cytotoxic and genotoxic hydrogen sulfide as a terminal product. This leads has been shown experimentally to lead to chronic mucosal inflammation and hyperproliferation, a state that increases cancer risk. In contrast, Africans are protected by high populations of methanogens which thrive in high carbohydrate, meat-free conditions and produce the non-toxic terminal product, methane. Our studies have also showed higher populations of secondary bile salt producing bacteria in AAs which are stimulated by high animal fat diets to produce carcinogenic secondary bile salts. In contrast, a high resistant starch diet stimulates mucosal-protective Lactobacillus species were, indeed, found to be more common in Africans. These observations have lead to our hypothesis that the risk of developing cancer of the colon is determined by the interaction between diet and resident microbiota, which influences the level of chronic inflammation and epithelial proliferation - and therefore cancer risk - in the colonic mucosa. In the present proposal, we plan to substantiate this hypothesis by studying 20 healthy middle aged subjects from the population of AAs in the Pittsburgh area and compare them to the same number of Africans before and 2 weeks after dietary switch. Specifically, we will change the AA diet to a high resistant starch, low meat diet and the African diet to a high red meat, low carbohydrate "westernized" diet. If our hypothesis is supported, we will expect to observe in the AA group an increase in methanogenesis and a reduction in colonic SRBs and hydrogen sulfide production, resulting in a reduction in mucosal inflammation and colonic epithelial proliferation, our primary biomarker of cancer risk. In contrast, we will expect to find increased SRB population growth in Africans with suppression of methanogenesis. Microarray analysis of mucosal gene expression, followed up by RT- PCR confirmation will be employed to identify novel pathways that may explain the mechanisms that link diet, bacterial metabolism, inflammation, and hyper-proliferation. Our findings will provide insight into how the diet can be manipulated to modify microbiota to promote mucosal health, and therefore reduce colon cancer risk, diminish health care costs related to diagnosis and treatment, and decrease the unacceptably high present morbidity and mortality from this disease in African Americans. PUBLIC HEALTH RELEVANCE: Colon cancer is the second leading cause of cancer death in the USA, and compared to other U.S. racial groups African-Americans have the highest incidence (70 per 100,000 of the population) and mortality. These statistics contrast sharply from those reported in native Africans where incidence rates are <1 per 100,000. Our previous studies have suggested the difference can be attributed to the relatively higher meat and animal fat intake by African Americans and the higher resistant starch intake by Africans.

描述（由申请人提供）：癌症发病率的地理差异一般可归因于环境原因，特别是饮食。我们关注的是，非洲裔美国人（AA）在美国结肠癌的发病率（c1：70，000）和死亡率最高的原因是由于饮食因素，因为非洲土著人的饮食非常不同，几乎从未患过这种疾病（<1：100，000）。我们在这两个社区的研究，得到了大量实验证据的支持，表明原因可能在于AA对红肉的高饮食摄入，这增加了硫还原菌（SRB）的微生物群数量，从而产生细胞毒性和遗传毒性硫化氢作为最终产物。实验表明，这会导致慢性粘膜炎症和过度增殖，这是一种增加癌症风险的状态。相比之下，非洲人受到大量产甲烷菌的保护，这些产甲烷菌在高碳水化合物，无肉的条件下茁壮成长，并产生无毒的最终产品甲烷。我们的研究还表明，在高动物脂肪饮食刺激下，AA中产生次级胆汁盐的细菌数量较高，从而产生致癌的次级胆汁盐。相比之下，高抗性淀粉饮食刺激粘膜保护乳酸菌物种，确实，发现在非洲人中更常见。这些观察结果导致我们的假设，即发展结肠癌的风险是由饮食和居民微生物群之间的相互作用决定的，这会影响结肠粘膜中慢性炎症和上皮增殖的水平，从而影响癌症风险。在本提案中，我们计划通过研究匹兹堡地区AA人群中的20名健康中年受试者来证实这一假设，并将他们与饮食转换前和2周后相同数量的非洲人进行比较。具体来说，我们将改变AA饮食高抗性淀粉，低肉类饮食和非洲饮食高红肉，低碳水化合物的“西化”饮食。如果我们的假设得到支持，我们将期望在AA组中观察到甲烷生成的增加和结肠SRB和硫化氢产生的减少，导致粘膜炎症和结肠上皮增殖的减少，这是我们癌症风险的主要生物标志物。相比之下，我们将期望在非洲人中发现增加的SRB人口增长与甲烷生成的抑制。将采用粘膜基因表达的微阵列分析，随后进行RT-PCR确认，以鉴定可能解释饮食、细菌代谢、炎症和过度增殖相关机制的新途径。我们的研究结果将深入了解如何操纵饮食来改变微生物群以促进粘膜健康，从而降低结肠癌风险，减少与诊断和治疗相关的医疗保健成本，并降低非洲裔美国人这种疾病目前不可接受的高发病率和死亡率。公共卫生关系：结肠癌是美国癌症死亡的第二大原因，与美国其他种族相比，非洲裔美国人的发病率和死亡率最高（每10万人中有70人）。这些统计数字与非洲土著人报告的数字形成鲜明对比，非洲土著人的发病率低于十万分之一。我们以前的研究表明，这种差异可以归因于非洲裔美国人相对较高的肉类和动物脂肪摄入量以及非洲人较高的抗性淀粉摄入量。